In vitro techniques have been developed to study the cellular and molecular mechanisms by which osseous metastases are formed in patients with breast cancer and other solid tumors. We have found that human breast cancer cells resorb bone directly. We also wish to identify the humoral factors produced by fresh human tumor cells in culture which stimulate bone resorption by using the media harvested from tumor cells cultured in semi-solid media. We plan to determine the mechanism of bone resorption and to characterize the relationship between hypercalcemia, increased nephrogenous cyclic AMP generation and hypophosphatemia in two hypercalcemic animal tumor models, the rat leydig cell tumor and the Walker 26 carcinosarcoma. We plan to determine the mechanis of hormone-related hypercalcemia in patients with breast cancer using cultured human breast cancer cells incubated with estrogens and antiestrogens. We plan to continue our studies on the bone-derived chemotactic factor for breast cancer cells, including its biological and chemical characterization and identification of agents which inhibit it. We plan to identify factors released by human and animal tumor cells which stimulate bone formation and cause osteosclerotic metastases.